استعداد ابتلا به استرس در موش های ترانس ژنیک با تظاهرات بالای ژن TrkC، یک مدل از اختلال پانیک

Stressful life events increase the susceptibility for subsequent onset of psychiatric disorders in humans. Previous research has implicated neurotrophins in the onset of some stress-related diseases, such as major depression disorder, post-traumatic stress disorder or panic disorder. We have tested the hypothesis that the neurotrophin-3 (NT-3)/TrkC system is a genetic interface mediating the deleterious effects of stress on the initiation of panic disorder and other pathologies. To this aim, we have analyzed the functionality of HPA axis and the behavioral consequences of different types of stressful conditions in a mouse model of panic disorder, which overexpresses TrkC, the high affinity-receptor for NT-3 (TgNTRK3). Our results reveal that TgNTRK3 mice exhibit an altered circadian corticosterone rhythm that is reversed by clonidine treatment, but normal expression of genes involved in the control of the hypothalamus–pituitary–adrenal (HPA) axis (CRH, GR) and normal corticosterone response to acute and chronic stressors. In contrast, they exhibit an altered pattern of activation of stress-related brain areas and showed enhanced anxiety-related behavior and more passive strategies than wild types under some chronic stress conditions. We conclude that TgNTRK3 mice present differences in their response to stress characterized by subtle changes in the HPA axis, marked changes in acute stress-induced brain activation and altered coping strategies, suggesting a key role of TrkC receptor in the stress neural circuitry and in the behavioral consequences of chronic stress.

Stress susceptibility in humans is a major risk factor to develop neuropsychiatric disorders, and a contributing factor to post-traumatic stress disorder (PTSD), major depressive disorder (MDD) or panic disorder (PAND) (Rubin, 1989, Schreiber et al., 1996 and Yehuda, 2002). In addition to an inability to develop adequate coping strategies (Goldstein et al., 1987 and Stokes, 1995), these stress-related disorders are often accompanied by alterations of the central and peripheral components of the hypothalamus–pituitary–adrenal (HPA) axis. However, such alterations differ among the three pathologies. Thus, PTSD and MDD appears to be characterized by higher brain corticotrophin-releasing hormone (CRH) activity, but peripheral HPA hormones, particularly cortisol, are elevated in MDD, whereas hypocortisolism has been observed in some PTSD populations (Belmaker and Agam, 2008, de Kloet et al., 2006, Kellner and Yehuda, 1999 and Stam, 2007). In contrast, PAND is characterized by normal brain CRH activity, and normal or high plasma cortisol levels (Abelson et al., 2007 and Kellner and Yehuda, 1999). Recently, molecules involved in the development and plasticity of the central nervous system such as neurotrophins, have been suggested to play a role as etiological or predisposing factors in stress-related disorders (Duman and Monteggia, 2006, Gratacós et al., 2007 and Govindarajan et al., 2006). In humans, linkage studies have revealed that single nucleotide polymorphisms in the neurotrophin-3 (NT-3) receptor, the neurotrophin tyrosine kinase receptor 3 (NTRK3) gene, encoding for TrkC, may be involved in the pathophysiology of PAND ( Armengol et al., 2002) and obsessive–compulsive disorder (OCD) ( Alonso et al., 2008 and Mercader et al., 2008). In addition, genome scan studies ( Holmans et al., 2004 and McGuffin et al., 2005) showed a high evidence of linkage of the 15q25.3–26.2 region, that contains NTRK3 gene, with recurrent MDD of early-onset, confirmed by linkage disequilibrium mapping of this region ( Feng et al., 2008 and Verma et al., 2008). These results suggest that NTRK3 may have a function in the pathophysiology of stress-related disorders, probably by mediating or potentiating the effect of negative or stressful life events. Moreover, the expression of NT-3 and TrkC is ubiquitously distributed throughout the brain, but their mRNAs have been predominantly detected in the hippocampus ( Lamballe et al., 1994), a region that plays a modulatory role in the HPA axis functionality and in situ hybridization studies have demonstrated TrkC expression in regions involved in the initiation and modulation of the stress response, such as the paraventricular nucleus of the hypothalamus (PVN) and other hypothalamic nuclei, at both prenatal and postnatal stages ( Hassink et al., 1999). It has been hypothesized that the alteration of neurotrophin expression driven by stress could be involved in the onset and pathophysiology of stress-related disorders, since they play an important role in translating neuronal activity into biochemical and structural plasticity (Lindholm et al., 1994). In fact, exposure to stress alters neurotrophin expression in brain (Pizarro et al., 2004, Smith et al., 1995a, Smith et al., 1995b and Smith et al., 1995c). Specifically, intense stressful stimuli, such as acute or chronic immobilization, reduce BDNF (Adlard et al., 2004, Murakami et al., 2005 and Smith et al., 1995c) and increase NT-3 mRNA levels in the hippocampus (Smith et al., 1995c). In addition, early maternal separation followed by two acute exposures to stress in adolescence and adulthood, has been reported to increase NT-3 levels in the dorsal hippocampus (Faure et al., 2006) and glucocorticoids regulate neurotrophin mRNA levels in the cerebral cortex and hippocampus (Barbany and Persson, 1992, Hansson et al., 2000, Pizarro et al., 2004, Smith et al., 1995a, Smith et al., 1995b and Smith et al., 1995c). Regarding neurotrophin receptors, TrkB expression is also affected by glucocorticoids (Roskoden et al., 2004 and Schaaf et al., 1998) and stress (Ueyama et al., 1997), and early postnatal corticosterone increases TrkC mRNA levels in the rat hippocampus (Roskoden et al., 2004). Previous studies in our laboratory have validated for PAND TgNTRK3 mice, a transgenic mouse model that overexpresses TrkC. These mice show mild anxiety-like behavior in some tests, increased panic reaction and higher sensitivity to anxiolytics (Dierssen et al., 2006). Besides we detected an increase in locus coeruleus (LC) noradrenergic (NAergic) neurons (Dierssen et al., 2006), increased cellularity in the amygdala and hippocampus (Sahun et al., 2007a), and a differential neuronal activation pattern to anxiogenic drugs (Sahun et al., 2007b). Finally, electrophysiological studies revealed an increase in basal firing rate in the LC (Gallego et al., submitted for publication), and increased paired pulse facilitation and long term potentiation (LTP) in the hippocampus (Sahun et al., 2007a), which may influence for certain aspects of stress-related information processing. We here propose that the dysregulation of NT-3/TrkC, which we previously demonstrated to be involved in PAND pathophysiology (Dierssen et al., 2006 and Sahun et al., 2007a), could be important for the altered adaptation or sensitization to chronic stress in mood and anxiety-related disorders. To explore this possibility we have used TgNTRK3 mice (Dierssen et al., 2006), exploring the responses of these mice to different stressor intensities at the hormone, gene expression, brain activation and behavioral levels.